TUMOUR mutations could be used to predict patients’ responses to cancer treatment drugs, according to the results of a recent study. A group of researchers from the Memorial Sloan Kettering Cancer Center worked with the Johns Hopkins Kimmel Cancer Center, including the Bloomberg-Kimmel Institute for Cancer Immunotherapy, to find an explanation for why some patients do not respond to cancer immunotherapy. They found that a higher degree of microsatellite instability (MSI) increased the likelihood of a response to treatment.
Cancer treatment research has seen a rise in the success of checkpoint inhibitor drugs, but in patients who have mutations, around 50% fail to respond to the treatment. In this study, MSI intensity was found to play a role in the likelihood of tumours responding to immunotherapy and that tumours with higher MSI also have a higher degree of DNA alterations from repeated cell divisions, particularly insertion and deletion mutations.
Tumours were created from mouse melanoma and colorectal cancer cell lines, edited with CRISPR-Cas9. They were created with mismatch repair deficiency and then grown for a certain period of time: 4 weeks (MSI-intermediate cell lines) or 4 months (MSI-high cell lines), which had more indel and missense mutations than the intermediate and original cell lines. Live mice had these cell lines implanted into their flanks and then received either anti-PD-1 checkpoint inhibitors that turn off the immune cell brakes that stop the cancer cell immune response, or a mock treatment.
The combination of MSI-high cell line and anti-PD-1 treatment resulted in a higher decrease in tumour volume. After 24 days, tumour-infiltrating lymphocytes were measured, and a statistically significant increase was found in this same combination. They also found a reduction in indel and missense mutations in the tumours. Clinical data from three cancer patient cohorts was also examined and demonstrated a trend of increased immune activity in MSI-high tumours compared with MSI-low tumours.
Researcher Rajarsi Mandal, Director of the Head and Neck Cancer Immunotherapy Research Program, Bloomberg~Kimmel Institute for Cancer Immunotherapy, discussed the study: “This genetic ‘signature’ potentially could serve as a novel biomarker, akin to a crystal ball, to see which cancer patients may respond to immunotherapy.” Tumour biopsy and sequencing of DNA to study MSI intensity could be used when formulating treatment plans. Further research is needed to validate these findings, as recognised by the researchers. The research team want to explore the MSI-related immune response further, looking at the role of the innate immune system.
